Human gut organoids as translational research tools

The intestinal epithelium is a highly organised, self-renewing tissue with a proliferative crypt compartment and a differentiated villus. It is constantly exposed to complex microbiota, nutrients, immune cells etc. and this single cell layer is involved in the critical interface/crosstalk between the host and the environment.

Previously, most of the research was performed on 2D immortalised cancer cell lines which are genetically, metabolically and phenotypically different from in vivo cells. In 2009, Sato and colleagues developed the human organoid culture model wherein the epithelium forms self-organising, three-dimensional miniature organs that closely mimic in vivo conditions. 3D intestinal epithelial organoids (IEOs) can mirror structural alterations, mutational signatures, and gene expression changes between patient and patient-derived organoids. These organoids can be generated from cryopreserved human tissue and this has further increased the value of samples obtained both for routine clinical care and for specific research settings.

We have successfully generated IEOs from different gut segments of the human intestinal tract and have observed that these organoids display gut segment-specific features in vitro. IEOs provide scientists with unique opportunities to use these models as highly versatile translational research tools. Clinically, the model can be used for the development of noveltherapeutics, testing of existing drugs with an aim to personalise treatment based on responses as well as the use in regenerative medicine (Fig. 1). Intestinal organoid protocols can be adapted to push cellular homeostasis within the organoid toward specific cell fates.

This is another exciting application of the organoids to study rare cell types and how these contribute to human biology and disease.

In our group, we have shown disease-associated alterations in the epigenetic profile, in the primary epithelium of IBD patients. We were also able to demonstrate that IBD patient-derived IEOs retain their disease-specific DNA methylation signatures in culture. These findings strongly support the use of patient-derived IEO as translational research tool to advance our understanding of IBD pathogenesis and to develop improved approaches to manage these conditions.